It is now established that macrophages derived from blood monocytes play a role in the development of atherosclerotic lesions and are themselves precursors of many arterial foam cells. Form cells characteristically contain cytoplasmic droplets of cholesteryl ester which greater than or equal to 50 percent of the total cellular cholesterol content. Massive cholesteryl ester accumulation in macrophages in vitro can be induced by certain receptors mediating the uptake of cholesteryl ester-rich lipoproteins: the Beta-VLDL receptor (Beta-VLDL), the scavenger receptor (modified LDL with net negative charge), and the LDL-dextran sulfate receptor (LDL-dextran sulfate complexes). Our research indicates that LDL entering human monocyte-macrophages by the LDL receptor, however, does not cause massive cholesteryl ester accumulation. We propose to determine the role of both the scavenger and Beta-VLDL receptors in foam cell formation in humans and WHHL rabbits and characterize the determinants promoting ligand recognition by each of these receptors. We will establish the determinants and significance of cholesterol efflux in foam cell formation. We will determine the effect of calcium and calmodulin inhibitors on macrophage receptor activities and test the efficacy of these agents in preventing atherosclerosis in the WHHL rabbit. We will isolate and purify substances produced by lymphocytes that are extraordinarily potent inhibitors of receptor activities on macrophages, protecting the cells against cholesterol ester accumulation in vitro. We will determine the mechanism of action of these substances and test the efficacy of these substances in preventing atherosclerosis in cholesterol-fed and WHHL rabbits.